Release date: 2018-05-14
Yang Chunxi and Meng Linghua discuss issues
Guide process optimization
According to statistics from the National Cancer Center of China, malignant tumors, or cancer, are the leading cause of death among Chinese residents, and both morbidity and mortality are on the rise. It is imperative to improve the level of cancer treatment and speed up the research and development of new drugs.
At the beginning of this year, the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences issued a good news. The Ding Jian research group, Yang Chunyu research group, Meng Linghua research group and Shanghai Haihe Pharmaceutical Research and Development Co., Ltd. ("Haihe Pharmaceutical") have developed their own knowledge. CYH33, a new anti-tumor drug of the property rights, obtained the clinical trial approval issued by the State Food and Drug Administration and was approved for clinical trials.
"After arduous exploration, it is our mission to provide patients with more accurate therapeutic drugs for effective anti-tumor targets." Yang Chunxi said in an interview with the reporter of the Chinese Journal of Science.
The road to the birth of new drugs is not easy
"For those of us who do drugs, the most important thing is to meet the clinical needs of developing new drugs." Yang Chunxi said.
The phosphoinositide 3-kinase (PI3K) signaling pathway plays an irreplaceable regulatory role in tumorigenesis and progression. Since 2005, Yang Chunqi and the Chinese Academy of Engineering academician Ding Jian have started cooperation. "At the time, the research on new PI3K target drugs was almost blank. Ding and I were very optimistic about it." Yang Chunxi told reporters that although there were some compounds reported at the time, However, the drug is not good and the selectivity to PI3K is poor. "There are many scientific issues that need to be studied and validated for the PI3K target to be an effective anti-tumor target."
Yang Chunyu's research group is mainly responsible for the design, synthesis and optimization of compounds, and it is a prerequisite for how to quickly and efficiently find a "drug-like" lead compound for a target. Then, it is optimized and modified according to the results of in vitro and in vivo screening, and after various evaluations of drug-forming properties, it is finally determined to be a drug candidate.
In 2006, Meng Linghua, who completed post-doctoral training from the National Cancer Institute, joined the team of Academician Ding Jian. Under the guidance of Academician Ding Jian, the team members took the lead in establishing a relatively complete molecular and cellular level PI3K screening platform in China. In the frontier field, a screening and research system for PI3K subtype selective inhibitors has been established, and relevant methods have been granted Chinese patents. Based on the established drug screening system, the Menglinghua team worked closely with Yang Chunxi's medicinal chemistry team to find a new drug.
This work is like dancing with ballet. They designed and evaluated thousands of compounds. Yang Chunxi admits that there are many detours in the middle. "Some compounds have high activity at the enzyme level, but the cell level activity is not good; some compounds have good activity at the cellular level, but after the animal, the activity will not work, and some problems. The reason can be found, and some problems can not be found at the moment. Of course, if the animal has excellent activity, it is necessary to evaluate its pharmacokinetic properties, safety and so on."
The road of design and synthesis of compounds is full of ups and downs, and Yang Chunxi still remembers it. "Every day is about half a year is a failure," he recalls. The mother nucleus of CYH33 adopts an advantageous structure of medicinal chemistry. At the time, there were few methods reported in related literatures. "The difficulty in the synthesis of the mother nucleus structure is: if it is an electron donating group, it is relatively easy to synthesize, and we What is needed is an intermediate with an electron-withdrawing group. We tried all the methods of analog synthesis in the literature and could not provide satisfactory results."
Dr. Chen Yanhong, one of the inventors of the drug, was deeply touched. “It took almost a year to get the access line and get the target compound. Especially when building pyrrotriazine in key steps, I can't remember how many times I failed.â€
In the end, they developed a new synthetic route. After the results were published, they were rated as “highlight articles†by SYNFACTS magazine.
“In stepping forward, we will move forward step by step. When a small node succeeds, we will have a short moment of joy, which gives us more confidence and motivation to continue to cope with the challenges that follow,†said Yang Chunxi.
New drug with "Chinese characteristics"
The data show that in China, lung cancer, digestive tract cancer, breast cancer and other cancers are among the highest in cancer incidence and mortality, and are high-risk tumors in China.
"In terms of strategy, we focus on breaking through the characteristic tumors of Chinese races," Yang Chunxi said. Compared with similar drugs that have entered the phase III clinical trials internationally, CYH33 has shown more significant antitumor activity in vitro and in vivo. In particular, it exhibits excellent inhibitory activity against Chinese characteristic tumors.
In addition, the novel and unique superior structure is also a highlight of this new drug in technology research and development. Yang Chunxi told reporters that "CYH33 is a subtype selective inhibitor against phosphoinositide 3-kinase (PI3K) a. This structure is completely different from the existing a subtype inhibitor, with high selectivity and high activity. ."
In recent years, drug design based on superior structure has attracted more and more attention from pharmaceutical chemists. It is a structural fragment shared between different compounds acting on different receptors and can carry a variety of pharmacological activities. "In general, this structure is often found in various drugs, so its probability of becoming a drug is higher. The prospect is better." Yang Chunxi said.
PI3Ka plays a major role in the signaling pathway induced by growth factor stimulation, and only this subtype has activating mutations at high frequency in tumor tissues. In this regard, international studies have focused on PI3K pan-inhibitors or PI3K-mTOR dual inhibitors, but they all have the disadvantage of "dose-limiting toxicity."
Yang Chunxi said: "For PI3Ka subtype selective inhibitors, because PI3Ka is most frequently mutated and highly expressed in tumors, we have developed compounds specifically for this subtype, and its toxic side effects are relatively low."
The efficacy of the drug needs to be clinically verified
CYH33, a new anti-tumor drug, has entered the first phase of clinical trials. For researchers, the future is bright, but it is still tortuous.
"The huge species differences between humans and animals may lead to large differences in the effectiveness and safety of preclinical and clinical drugs. This is a difficult point in drug development worldwide, and CYH33 is also to be validated on humans. "Yang Chunxi said.
New drug clinical research should go through the clinical phase I, II, and III, and there are risks at every stage.
Meng Linghua told reporters that at present, they are looking for molecular markers in cooperation with the sea and drugs. "Screening patients by identifying molecular markers and monitoring the early treatment of patients can improve the accuracy and efficiency of treatment."
Meng Linghua mentioned that they are still working with CYH33 and some existing drugs for treating tumors in order to improve the efficacy.
In Yang Chunxuan's view, the development of the candidate new drug CYH33 involves cooperation among various disciplines and research groups such as chemistry, pharmacology, drug metabolism, safety evaluation, and preparation. It stands out as a candidate drug and cannot be separated from the various teams of the drug company. A close and efficient cooperation atmosphere.
"The follow-up research and development work can not be slack, and it may be necessary to wait until the final new drug is actually listed, sales, and the market is evaluated well, which is our true success." Yang Chunxi said. (Han Yang Mei Huang Xin)
Source: Science Network
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